Treatment of cancer using polypeptide bombesin/GRP antagonists

The pseudopeptides of formula (I) possess antagonist properties against bombesin or bombesin-related peptides (such as gastrin releasing peptide or Neuromdin C). The antagonists can be used in a medicament to treat cancer. (I) X-A1-A2-Trp-Ala-Val-Gly-His-Leu-psi-A9-Q Wherein; X is hydrogen, or a sin...

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1. Verfasser: SCHALLY, ANDREW VICTOR
Format: Patent
Sprache:eng
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Zusammenfassung:The pseudopeptides of formula (I) possess antagonist properties against bombesin or bombesin-related peptides (such as gastrin releasing peptide or Neuromdin C). The antagonists can be used in a medicament to treat cancer. (I) X-A1-A2-Trp-Ala-Val-Gly-His-Leu-psi-A9-Q Wherein; X is hydrogen, or a single bond linking the alpha amino group of A1 to the gamma carboxyl moiety on the 3-propionyl moiety of A2 when A2 is Glu, or a group of formula R1CO-, wherein R1 is selected from the groups consisting of: a) hydrogen, C1-10alkyl, phenyl or phenyl-C1-10-alkyl, p-Hl-phenyl, p-Hl-phenyl-C1-10-alkyl, naphthyl, naphthyl-C1-10-alkyl, indolyl, indolyl-C1-10-alkyl, pyridyl, pyridyl-C1-10-alkyl, thienyl, thienyl-C1-10-alkyl, cyclohexyl or cyclohexyl-C1-10-alkyl, where Hl=F, Cl, Br, OH, CH3 or OCH3; b) N(R2)(R3)-, wherein R2 is hydrogen, C1-10alkyl, phenyl or phenyl-C1-10-alkyl, and R3 is hydrogen or C1-10alkyl; c) R4O, wherein R4 is C1-10alkyl, phenyl or phenyl-C1-10-alkyl; A1 is a D- or L-amino acid residue selected from the group consisting of Phe, p-Hl-Phe, pGlu, Nal, Pal, Tpi, unsubstituted Trp or Trp substituted in the benzene ring by one or more members selected from the group consisting of F, Cl, Br, NH2 or C1-3alkyl; or A1 is a peptide bond linking the acyl moiety of R1CO- to the alpha amino moiety of A2, provided X=R1CO; A2 is Gln, Glu[-], Glu(Y) or His, wherein, when X is a single bond and A2 is Glu[-], [-] is a single bond linking the alpha amino group of A1 with the gamma carboxyl group of the 3-propionyl moiety of A2; Y is -OR5 or -N(R6)(R7), wherein R5 is hydrogen, C1-3alkyl or phenyl; R6 is hydrogen or C1-3alkyl; and R7 is hydrogen, C1-3alkyl or -NHCONH2; Leu-psi is a reduced form of Leu, wherein the C=O moiety of Leu is replaced with -CH2- such that there is a pseudopeptide bond of this -CH2- moiety with the alpha amino moiety of the adjacent A9 residue; A9 is Tac, MTac, or DMTac; and Q is NH2 or OQ1, where Q1 is hydrogen, C1-10alkyl, phenyl or phenyl-C1-10-alkyl.